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Keywords:

  • angiotensin II;
  • hepatic stellate cell;
  • liver;
  • MAPK;
  • Nox;
  • TGF-β

AII (angiotensin II) is a vasoactive peptide that plays an important role in the development of liver fibrosis mainly by regulating profibrotic cytokine expression such as TGF-β (transforming growth factor-β). Activated HSCs (hepatic stellate cells) are the major cell type responsible for ECM (extracellular matrix) deposition during liver fibrosis and are also a target for AII and TGF-β actions. Here, we studied the effect of AII on the mRNA levels of TGF-β isoforms in primary cultures of rat HSCs. Both quiescent and activated HSCs were stimulated with AII for different time periods, and mRNA levels of TGF-β1, TGF-β2 and TGF-β3 isoforms were evaluated using RNaseI protection assay. The mRNA levels of all TGF-β isoforms, particularly TGF-β2 and TGF-β3, were increased after AII treatment in activated HSCs. In addition, activated HSCs were able to produce active TGF-β protein after AII treatment. The mRNA expression of TGF-β isoforms induced by AII required both ERK1/2 and Nox (NADPH oxidase) activation but not PKC (protein kinase C) participation. ERK1/2 activation induced by AII occurs via AT1 receptors, but independently of either PKC and Nox activation or EGFR (epidermal growth factor receptor) transactivation. Interestingly, AII has a similar effect on TGF-β expression in quiescent HSCs, although it has a smaller but significant effect on ERK1/2 activation in these cells.